Project Summary/Abstract: Molecular Therapeutics (MT) The goal of the Molecular Therapeutics (MT) Program is to identify therapeutic targets, drugs, and strategies, and to facilitate the translation of Dartmouth-investigator hypotheses into clinical trials. The research interests of the program faculty cover the full spectrum of investigations in molecular therapeutics and include synthesis of novel compounds as research tools and potential therapeutics; investigation of novel targets for therapy; assessment of predictors of disease progression or drug response; and proof-of-concept and therapeutic early phase clinical trials. The MT program currently has 30 members from 9 different departments whose research foci can be described under the following four scientific themes: (1) Synthesis and discovery of novel compounds and potential cancer drugs, (2) Interrogation of potential new targets and therapeutic strategies, (3) Development of biomarkers for cancer diagnosis and prediction of treatment response, and (4) Development of hypothesis-based cancer clinical trials. These four research themes do not exist as separate entities. There is extensive interaction between them, as novel drugs and compounds are used to interrogate novel targets, novel biomarkers are being identified, and these advances are being translated into molecular proof-of- principle clinical trials. The interactions across this spectrum are catalyzed by the interactive environment generated by activities of the MT program, its deep involvement in the Early Phase Trials Clinical Oncology Group (EPTCOG), and by the continual nurturing and mentoring of program members by the Program Co- Directors. This work results in extensive collaborations across the entire spectrum of molecular therapeutics, as evidenced by joint grants and publications. Major contributions of the program to the NCCC mission have been the facilitation of discoveries promising new therapeutic approaches, the translation of Dartmouth investigator hypotheses into clinical trials, and the accrual of patients to such studies. In addition, NCCC has made substantial commitment to improving the depth and breadth of research and clinical translation in the MT program through support of shared resources, financially supporting many of the costs associated with early- phase/proof-of-principle clinical trials, and strategic recruitment of new investigators. For example, over the past 5 years, the membership of the program has evolved with the successful recruitment of outstanding new faculty in the biological laboratory sciences (Miller, Kurokawa), chemistry (Micalizio, Wu), and in clinical/translational investigations (Danilov, Lansigan, Smith). More than 363 cancer-related articles have been published over the reporting period (54 [15%] in high impact journals), many of them representing intra- program (69=19%) or inter-program (107=29%) collaboration. These collaborations involve 29 MT program members and 63 NCCC members, almost equally distributed between the other 5 NCCC research programs. Total funding for the program currently is $8.0M, of which $6.0M is peer-reviewed and $3.4M is from NCI.